Embodiments of this invention are related generally to physiology and medicine. More specifically, this invention is related to aldose reductase inhibitors (ARIs) and their use in treating chronic obstructive pulmonary disease (COPD).
Aldose reductase (AR) catalyzes the reduction of a wide range of aldehydes (Bhatnager and Srivastava, Biochem Med Metab Biol. 48(2):91-121, 1992). The substrates of the enzyme range from aromatic and aliphatic aldehydes to aldoses such as glucose, galactose, and ribose. The reduction of glucose by AR is particularly significant during hyperglycemia and increased flux of glucose via AR has been etiologically linked to the development of secondary diabetic complications (Bhatnager and Srivastava, Biochem Med Metab Biol. 48(2):91-121, 1992; Yabe-Nishimura, Pharmacol Rev. 50(1):21-33, 1998). However, recent studies showing that AR is an excellent catalyst for the reduction of lipid peroxidation-derived aldehydes and their glutathione conjugates (Srivastava et al., Biochem Biophys Res Commun. 217:741-746, 1995; Vander Jagt et al., Biochim Biophys Acta. 1249(2):117-26, 1995; Srivastava et al., Biochemistry. 37(37):12909-17, 1998; Srivastava et al., Adv Exp Med. Biol. 463:501-7, 1999; Dixit et al., J Biol. Chem. 275:21587-21595, 2000; Ramana et al., Biochemistry. 39:12172-12180, 2000) suggest that in contrast to its injurious role during diabetes, under normal glucose concentration, AR may be involved in protection against oxidative and electrophilic stress. The antioxidant role of AR is consistent with the observations that in a variety of cell types AR is upregulated by oxidants such as hydrogen peroxide (Spycher et al., FASEB J. 11(2):181-8, 1997), lipid peroxidation-derived aldehydes (Ruef et al., Arterioscler Thromb Vasc Biol. 20(7):1745-52, 2000; Rittner et al., J Clin Invest. 103(7):1007-13, 1999), advanced glycosylation end products (Nakamura et al., Free Radic Biol Med. 29(1):17-25, 2000) and nitric oxide (Seo et al., J Biol. Chem. 275(39):30355-62, 2000). The expression of the enzyme is also increased under several pathological conditions associated with increased oxidative or electrophilic stress such as iron overload (Barisani et al., FEBS Lett. 469(2-3):208-12, 2000), alcoholic liver disease (O'Connor et al., Biochem J. 343 Pt 2:487-504, 1999), heart failure (Yang et al., Circulation. 102(25):3046-52, 2000), myocardial ischemia (Shinmura et al., Proc Natl Acad Sci USA. 97(18):10197-202, 2000), vascular inflammation (Rittner et al., J Clin Invest. 103(7):1007-13, 1999) and restenosis (Ruef et al., Arterioscler Thromb Vasc Biol. 20(7):1745-52, 2000), and various forms of cancer.
Inhibitors of aldose reductase have been indicated for some conditions and diseases, such as diabetes complications, ischemic damage to non-cardiac tissue, Huntington's disease. See U.S. Pat. Nos. 6,696,407, 6,127,367, 6,380,200, which are all hereby incorporated by reference. In some cases, the role in which aldose reductase plays in mechanisms involved in the condition or disease is known. For example, in U.S. Pat. No. 6,696,407 indicates that an aldose reductase inhibitors increase striatal ciliary neurotrophic factor (CNTF), which has ramifications for the treatment of Huntington's Disease. In other cases, however, the way in which aldose reductase or aldose reductase inhibitors work with respect to a particular disease or condition is not known.
Therefore, the role of aldose reductase in a number of diseases and conditions requires elucidation, as patients with these diseases and conditions continue to require new treatments. Thus, there is a need for preventative and therapeutic methods involving aldose reductase and aldose reductase inhibitors.